The present disclosure generally relates to cancer and more particularly to pre-operatively locating and differentiating cancer involved lymph nodes for cancer patient prognostication or patient management.
In a story entitled “Colon Cancer Care found Lacking,” by Lauran Neergard, Associated Press (Sep. 10, 2008), published in the Boston Globe, Neergard reports that nearly two-thirds of hospitals fail to check colon cancer patients well enough for signs that their tumor is spreading, says a study that advises patients to ask about this mark of quality care before surgery. National guidelines say that when colon cancer is removed, doctors should check at least 12 lymph nodes for signs of spread. Checking fewer than 12 isn't considered enough to be sure the cancer is contained. It is estimated that just 38% (of hospitals) fully comply with this guideline. Dr. Kyle Bilimoria of Northwestern University and The American College of Surgeons, and others describe shortcomings associated with colon cancer patient treatment in a study of 1,300 hospitals: “Some 148,000 Americans are diagnosed annually. For many, the node check can be crucial. Whether cancer has entered these doorways to the rest of the body is an important factor in long-term survival—and thus helps doctors decide who gets chemotherapy after surgery and who can skip it . . . . Patients who could benefit from additional chemotherapy may not be getting complete treatment and have a higher chance of relapse,” said Dr. Durado Brooks of the American Cancer Society, who was not involved with the study. “It is something that consumers need to begin asking . . . . Frankly, that is most likely to change medical practice.” “To check enough nodes, surgeons must remove enough of the fat tissue by the colon where they hide, and pathologists must painstakingly dissect that tissue to find the tiny nodes. Surgeons frequently tell of getting a pathology report of four clean nodes and asking the pathologist to find more, “and lo and behold, one of those additional nodes turns out to be positive,” Bilimoria said.
In an article entitle, “Checking More Lymph Nodes Linked to Cancer Patient Survival”, ScienceDaily (Jul. 23, 2008) reports: Why do patients with gastric or pancreatic cancer live longer when they are treated at cancer centers or high-volume hospitals than patients treated at low-volume or community hospitals? The report continues that new research from Northwestern University's Feinberg School of Medicine found that cancer patients have more lymph nodes examined for the spread of their disease if they are treated at hospitals performing more cancer surgeries or those designated as comprehensive cancer centers. Lymph node mestatases (indicating the spread of cancer) have been shown to predict patients' prognosis after cancer tissue is removed from the stomach or pancreas. If too few nodes are examined for malignant cells, a patient's cancer may be incorrectly classified, which alters the prognosis, treatment decisions and eligibility for clinical trials.
Referring to the Jul. 23, 2008 ScienceDaily article, “The differences in nodal evaluation may contribute to improved long-term outcomes at cancer centers and high-volume hospitals for patients with gastric and pancreatic cancer,” said Karl Bilimoria, MD, lead author of the paper and a surgical resident at the Feinberg School.” Bilimoria goes on to say: “Every reasonable attempt should be made to assess the optimal number of lymph nodes to accurately diagnose stage disease in patients with gastric and pancreatic cancer,” said Bilimoria, who also is a research fellow at the American College of Surgeons. “The status of patients' lymph nodes is a powerful predictor of their outcome.” July 2008 issue of Archives of Surgery. 
Molecularimaging.net September 2008—Vol 2 No. 5, Molecular Imaging Insight (Sponsored by an educational grant from Siemens) states that the primary molecular imaging modalities—PET and SPECT—rely on biomarkers, or tracers, to help detect and localized disease. Current biomarkers, primarily FDG-based, which are used in oncologic and Alzheimer's applications, and cardiac tracers like 99mTc-Sestamibi, Rubidium-82 and N13-Ammonia, demonstrate the potential of molecular imaging. Used in conjunction with PET, FDG indicates metabolic activity associated with malignancies and is used in diagnosis, staging and monitoring treatment of various cancers. Despite their proven utility, there are limits to the currently available tracers. FDG uptake can be increased in benign disorders such as inflammation or infection potentially resulting in false positive results for cancer.
In a related article from the same issue of Molecular Imaging Insight, comes this discussion about disease detection and staging. PET scanning can be used to detect established tumors, but TAG positive lymph nodes are not detectable with today's PET agents. Also, PET agents produce non-specific positive results in the brain, heart, kidney, and inflammatory tissues. FDG opened the door and remains the gold standard for current oncology PET applications. It is approved for diagnosis and staging for a variety of types of cancer. But FDG also is associated with some shortcomings that make it a less than ideal tracer. For example, FDG is not highly specific. It does not always discriminate malignant from benign tumors, and uptake can be high in areas of inflammation. Consequently, it can be difficult for physicians to detect initial and recurrent disease in some patients, particularly those with inflammatory disease or scar tissue. In some cases, radiation therapy can produce scar tissue, decreasing the utility of FDG PET for disease monitoring as the tissue can obscure lesions. Molecularimaging.net September 2008—Vol 2 No. 5, Molecular Imaging Insight 
FDG, then, is a sugar that is not a cancer-specific targeting agent. Tissues and organs that normally metabolize glucose—brain, heart, muscle, kidney, bladder, bowel—are visualized. Also imaged are inflammatory stricken tissue, infectious agents, and post-trauma engaged tissues.
FDG is indeed very easy to use. It is commercially available for PET scan. PET scan with FDG is a molecular imaging tool of the unique biochemical changes in tumors. 18F has a very short half-life (half-life 110 min.), which makes it a better isotope for handling and disposal within the operation room than 125I (half-life 60 days) in RIGS. However, 18F is not feasible for labeling of anti-TAG-72 antibody as it is in RIGS due the short half-life of 18F and long half-life of anti-TAG-72 antibodies, unless a two step system with 18F and anti-TAG-72 antibodies is modified for PET/CT image-guided surgery.
There are several limitations for PET and PET/CT image-guided surgery. First, this technology tends to detect the later stage tumors with resultant higher glycolysis rates. Therefore, this technology is somewhat limited by a finite level of tumor volume detection, such that small volume, microscopic, occult disease will be beneath the level of detection capable by PET and PET/CT image-guided surgery. Second, FDG is also taken up by many normal tissues and in many normal physiological conditions, such as is seen with brain, heart, kidney, muscle and adipose tissues. Duxin Sun, Mark Bloomston, George Hinkle, Osama Habib Al-Saif, Nathan C. Hall, Stephen P. Povoski, Mark W. Arnold, and Edward W. Martin Jr., “Advantages And Limitations Of Pet/Ct Image-Guided Surgery In Comparison To Hand-Held Detection Probe In RIGS”, Journal of Surgical Oncology 2007; 96:297-308.
Newer biomarkers, such as FLT (18F-3′-fluoro-3′-deoxy-L-thymidine), measure cell proliferation or cancer growth. Studies rate FLT as a better marker for tumor proliferation than FDG, but its uptake in cancer cells is lower than that of FDG. This means that whereas FDG does not generally detect tumors smaller than 5 mm, or lymph nodes, FLT is even worse in the cancer detection category.
Journal of Nuclear Medicine 2004, vol. 45, No. 9, pp 1509-1518; authors Maha Torabi, Suzanne L. Aquino, Mukesh G. Harisinghani, state:                The accurate identification and characterization of lymph nodes by imaging has important therapeutic and prognostic significance in patients with newly diagnosed cancers. The presence of nodal metastases limits the therapeutic options and also generally indicates worse prognosis in patients. Thus, it becomes crucial to have this information before commencing therapy. Current cross-sectional imaging modalities rely on insensitive size and morphologic criteria and, thus, lack the desired accuracy for characterizing lymph nodes. This is mainly because metastases can be present in non-enlarged lymph nodes and not all enlarged nodes are malignant. PET has overcome some of these limitations but is still constrained by current resolution limits for small nodal metastases. This has fueled the development of targeted techniques for nodal imaging and characterization as outlined in this article.        
Edmond S. Kassis, MD; Section of Thoracic Surgery, University of Pittsburgh Medical Center has been reported as saying that conventional scanning is inaccurate in over 40% of patients, as reported by Dr. Krasnack at the University of Maryland and by his group at the University of Pittsburgh. Endoscopic ultrasound is accurate in assessing the depth of tumor invasion, but its utility in detecting lymph node metastases has been questioned. Minimally invasive surgical staging has been shown by his group to be accurate, but requires general anesthesia and extensive lymph node dissection to avoid sampling errors, and requires a 24 to 48-hour hospital stay. Also, histological examination may miss small foci of metastatic disease, since there have been reports where up to 20% of histologically negative lymph nodes are positive on re-examination, which suggests a significant sampling error by pathologists. His group reports finding PET scanning to be useful in detecting distant metastatic disease, but only 44% sensitive in the detection of lymph node metastases.
Duxin Sun, Mark Bloomston, George Hinkle, Osama Habib Al-Saif, Nathan C. Hall, Stephen P. Povoski, Mark W. Arnold, and Edward W. Martin Jr., Journal of Surgical Oncology 2007; 96:297-308, in an article entitled “Radioimmunoguided Surgery (RIGS), PET/CT Image-Guided Surgery, and Fluorescence Image-Guided Surgery: Past, Present, and Future”, state:                FDG is indeed very easy to use. It is commercially available for PET scan. PET scan with FDG is a molecular imaging tool of the unique biochemical changes in tumors. 18F has a very short half-life (half-life 110 min.), which makes it a better isotope for handling and disposal within the operation room than 125I (half-life 60 days) in RIGS. However, 18F is not feasible for labeling of anti-TAG-72 antibody as it is in RIGS due the short half-life of 18F and long half-life of anti-TAG-72 antibodies, unless a two step system with 18F and anti-TAG-72 antibodies is modified for PET/CT image-guided surgery.        There are several limitations for PET and PET/CT image-guided surgery. First, this technology tends to detect the later stage tumors with resultant higher glycolysis rates. Therefore, this technology is somewhat limited by a finite level of tumor volume detection, such that small volume, microscopic, occult disease will be beneath the level of detection capable by PET and PET/CT image-guided surgery. Second, FDG is also taken up by many normal tissues and in many normal physiological conditions, such as is seen with brain, heart, kidney, muscle and adipose tissues.These authors conclude:        Humanized HuCC49ΔCH2 is the optimal antibody for tumor detection and has no HAMA response. RIGS with anti-TAG-72 antibodies [HuCC49ΔCH2] not only detects gross tumor, but also allows for precise detection and localization of occult disease within adjacent tissues and regional lymph nodes. The successful detection and subsequent removal of such occult disease in cancer patients significantly improve the 10-year survival.        
Ismet Sarikaya, Stephen P Povoski, Osama H Al-Saif, Ergun Kocak, Mark Bloomston, Steven Marsh, Zongjian Cao, Douglas A Murrey, Jun Zhang, Nathan C Hall, Michael V Knopp, and Edward W Martin, Jr., World J Surg Oncol. 2007; 5: 80, Published online Jul. 16, 2007. doi: 10.1186/1477-7819-5-80, in an article entitled, “Combined use of preoperative 18F FDG-PET imaging and intraoperative gamma probe detection for accurate assessment of tumor recurrence in patients with colorectal cancer”, state:                Numerous studies have demonstrated that FDG-PET has high sensitivity and high specificity for the detection of tumor recurrence in CRC patients with rising CEA levels in which there are no identifiable sites of tumor recurrence by standard anatomical imaging methods. Particularly, combined PET/CT is superior to CT and MRI for the detection of CRC local recurrences, as well as metastatic disease to the liver and other distant sites. However, the current FDG-PET scanning systems have several limitations. One of the most important limitations of FDG-PET scanning is its low sensitivity in detecting small sized lesions. FDG-PET has limited ability to detect lesions measuring less than 5 to 10 mm in size. A second limitation of FDG-PET imaging is the limited ability to assess local tumor invasion into the surrounding tissues. Strictly speaking, PET only imaging cannot identify local tumor invasion into the surrounding tissues secondary to the absence of anatomical correlation, as can be provided by combined PET/CT imaging. Nevertheless, while combined PET/CT imaging may be helpful in this regard if deeper tumor invasion is present, it will not be able to assess more limited tumor invasion. An additional limitation of FDG-PET imaging is its limited sensitivity for the detection of tumors that display a low metabolic activity. Finally, 18F FDG is limited by the fact that it is not cancer-specific, and resultant physiological uptake into benign tissue processes, such as infection and inflammation, can result in the identification of areas of increased uptake of 18F FDG.”        A recognizable limitation to both FDG-PET imaging and intraoperative GP [gamma probe] detection is the physiologic 18F FDG activity which can be demonstrated within nonmalignant tissues. This is especially evident in the scenario in which increased 18F FDG activity is seen in associated with infectious and/or inflammatory changes within nontumor-bearing tissues. Such a scenario creates false positive results with both preoperative FDG-PET imaging and intraoperative GP detection techniques. Likewise, it is well established that mucinous tumors are more difficult to identify with FDG-PET imaging, likely secondary to a lower metabolic activity of such tumors. It has been previously reported that the sensitivity of FDG-PET imaging for the detection of mucinous carcinoma is significantly lower than that of nonmucinous carcinoma (58% and 92%, respectively). This would also be the expectation for intraoperative GP detection of 18F FDG. Nevertheless, in our current study, the sites of tumor recurrence were accurately detected by both FDG-PET imaging and intraoperative GP detection in those three patients whose CRC recurrence represented mucinous adenocarcinoma. Although previous studies suggest that both preoperative FDG-PET imaging and intraoperative GP detection may not as effectively identify mucinous tumors, the surgeon's ability to position the intraoperative GP in close proximity to sites of suspected tumor recurrence may ultimately make intraoperative GP detection more efficient for the detection of mucinous tumors as compared to preoperative FDG-PET imaging.        
MacManus, et al, Department of Radiation Oncology, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia are reported as saying that PET scanning, because of its impressive sensitivity and accuracy, is being incorporated into the standard staging workup for many cancers. These include lung cancer, lymphomas, head and neck cancers, and oesophageal cancers. PET often provides incremental information about the patient's disease status, adding to the data obtained from structural imaging methods, such as, CT scan or MRI. PET commonly upstages patients into more advanced disease categories. Incorporation of PET information into the radiotherapy planning process has the potential to reduce the risks of geographic miss and can help minimize unnecessary irradiation of normal tissues. The best means of incorporating PET information into radiotherapy planning is uncertain, and considerable effort is being expended in this area of research.
The boundaries of some tumours can be very difficult to define, especially those that do not have clearly delineated margins on CT component of PET/CT. Motion of the patient on the couch top, which should be minimal with appropriate positioning and immobilization, and internal motion also contribute to the blurriness of PET images. Other factors that commonly cause difficulty include regions of low avidity in the tumour due to necrosis, the confounding effects of inflammation and infection that can give rise to intense uptake well within the range of standardized uptake value (SUV) seen in tumours, and poor contrast between tumours with a low SUV and adjacent normal structures. PET information is acquired over many respiratory and cardiac cycles and, therefore, an “average” position of the structures is imaged. In contrast, CT image is acquired virtually instantaneously and usually at a random phase of the respiratory cycle. Biomed Imaging Interv J 2007; 3(1):e4 doi: 10.2349/biij.3.1.e4
Maha Torabi, MD, Suzanne L. Aquino, MD; and Mukesh G. Harisinghani, MD, Department of Radiology, Massachusetts General Hospital, Boston, Mass. state that the accurate identification and characterization of lymph nodes by imaging has important therapeutic and prognostic significance in patients with newly diagnosed cancers. The presence of nodal metastases limits the therapeutic options and also generally indicates worse prognosis in patients. Thus, it becomes crucial to have this information before commencing therapy. Current cross-sectional imaging modalities rely on insensitive size and morphologic criteria and, thus, lack the desired accuracy for characterizing lymph nodes. This is mainly because metastases can be present in non-enlarged lymph nodes and not all enlarged nodes are malignant. PET has overcome some of these limitations but is still constrained by current resolution limits for small nodal metastases. This has fueled the development of targeted techniques for nodal imaging and characterization as outlined in this article. In the past few years, studies have shown that these newer imaging techniques can bridge some of the limitations of existing imaging for nodal characterization and thereby provide the much-needed staging information before the initiation of therapy. Journal of Nuclear Medicin. Vol. 45 No. 9 1509-1518.
U.S. Published Application 2007/0104717 discloses antibodies directed against CD55 and CD97 that can be used in PET scanning to detect and diagnose adenocarcinoma of the prostate (Paragraphs [0169], [0021]; Claim 18). Labels include Indium-111, Tc-99m, 131I, Gd (III) and Mn (II).
U.S. Published Application 2007/0042432 discloses a method of diagnosing adenocarcinoma using antibodies in PET scanners (Paragraphs [0140]-[0146]; Claim 14). No specific labels are shown.
U.S. Published Application 2006/0275212 discloses a method of diagnosing adenocarcinoma of the prostate using antibodies against prostate membrane antigen protein in a PET scanner (Paragraphs [0075]-[0076]; Claim 21). Labels include 131I, 111In 1231, 99mTc, 32P, 125I, 3H, 14C, and 188Rh.
U.S. Published Application 2006/0088539 discloses a method of using modified antibodies to prostate membrane antigen protein to detect adenocarcinoma of the prostate by PET scanning (Paragraphs [0435]-[0436]). Labels include 131I, 111In 123, 99mTc, 32P, 125I, 3H, 14C, and 188Rh.
Despite the perceived “advances” in cancer patient management by dint of PET scanning, John L. Marshall, MD (Chief, Division of Hematology/Oncology, Director of Development Therapeutics and GI Oncology, Lombardi Comprehensive Cancer Center, Georgetown University) takes a contrary position in “Practice-Changing Implications Today Compelling Data for Tomorrow” in a review of oncology PET scanning for the 44th Annual Meeting of the American Society of Clinical Oncology for their annual May/June 2008 meeting. In his review, Dr. Marshall notes that. “the role of PET scanning in the management of colorectal liver metastasis is controversial”. He continues that, “there is a relatively high false-positive and false-negative rate in patients with metastatic disease”. In fact, the “tumor size must be at least 1 cm to be reliably detected.” In a study reviewed, he notes, that “there still is a 28% rate of futile surgery performed.” He concludes that, “it is clear that we need even better imaging techniques to assist our decision making when attempting aggressive, invasive, although curative in intent, operations.” Supplement, Desk Reference, September 2008 Oncology, p. 17.
Thus, there still is a need to preferentially detect cancer-related lymph nodes, as well as tumors) preoperatively and in a facile manner, especially in order to enable the attending physician to determine the proper course of treatment (prognostication) of each such patient. It is to such need that the present disclosure is addressed.